HIV infection produces sweeping effects on the immune system; the consequences of these include the permissive expansion and replication of HIV, inflammatory injury and a profound immunodeficiency that facilitates the development of opportunistic infections. Based on the rationale that agents that promote a similar pattern of immune dysfunction could enhance HIV pathogenesis we have been investigating the impact of non-injection drugs of abuse on HIV pathogenesis. Using a mouse/human chimera model, we published the first direct evidence that cocaine enhances HIV replication and alters the expression and function of human immune cells in vivo. Although the impact of cocaine abuse on disease progression in HIV-positive individuals continues to be a major public health concern, increases in the use and abuse of another stimulant, methamphetamine (MA), has recently reached crisis proportions in both the HIV- seronegative and the HIV seropositive population. In effect, HIV and the use of MA have become a "double epidemic" over the past decade. Based on our previous work and what may be viewed as a public health imperative in the HIV-seropositve community, we have hypothesized that the immune modulating effects of MA will increase susceptibility to HIV infection and disease progression. To test this hypothesis, we will utilize a within-subjects study design to investigate and define the immunologic impact of experimentally administered MA in non-treatment seeking MA-dependent volunteers, who are either HIV-seropositive or HIV-seronegative. The specific aims include: Aim 1. To define immunologic parameters, pertinent to HIV infection, that may be modulated in chronic MA users following protracted use and following experimental administration of intravenous MA in a controlled clinical setting. Aim 2. To evaluate the significance of increased autonomic nervous system (ANS) activity as a potential mechanism by which MA may alter HIV infectivity and HIV-relevant immune parameters. Ultimately, defining the mechanisms underlying the interaction between MA and HIV may lead to the identification of novel pharmacotherapies designed to curb the accelerated disease progression in this unique population. [unreadable] [unreadable] [unreadable]